Abstract 15642: The Absence of Mitochondrial Fusion Protein Optic Atrophy (OPA) -1 Exacerbates Platelet Dysfunction
Mitochondrial dysfunction characterizes a large number of disorders associated with altered thrombosis. Preliminary studies indicated that transcripts encoding genes that regulate mitochondrial fusion, such as optic atrophy 1 (OPA-1) and mitofusin 2 proteins are altered in the platelets of diabetic humans and mice. Platelet hyperactivity and subsequent thrombosis is more prevalent in diabetic humans. Thus, we tested the hypothesis that altered mitochondrial dynamics could contribute to the pathophysiology of platelet dysfunction in these disorders. We therefore generated transgenic mice with platelet-specific knock out of optic atrophy 1 (OPA-1) by crossing mice harboring this floxed allele with mice that express platelet factor/chemokine receptor 4 Cre (PF4 Cre). Protein expression of OPA-1 long form was four-fold less than control platelets and the short form was undetectable in platelets from (OPA-1) lox/lox PF4 cre mice. Mitotracker staining revealed altered mitochondrial distribution in OPA-1 deficient platelets. Knockout platelets exhibited a 50 percent decrease in mitochondrial bioenergetics (oxygen consumption) compared to lox/lox control. Additionally, knockout platelets were significantly more activated in response to the thromboxane A2 (TP) receptor agonist (U46619 and the glycoprotein VI receptor agonist (Convulxin) compared to lox/lox controls. We therefore conclude that altered mitochondrial dynamics plays a pivotal role in platelet function and this model represents an important tool to study the relationship between mitochondrial dysfunction and the pathophysiology of platelet dysfunction.
- © 2013 by American Heart Association, Inc.